Drug & supplement interaction

St. John's Wort + Tapentadol

Tapentadol brand names: Nucynta, Nucynta ER.

Moderate Interaction
Medically reviewed by · Updated September 2026
The bottom line Moderate

Tapentadol falls into 3 drug categories that St. John's Wort can interact with; the most serious is rated moderate. Theoretically, St. John's wort might inhibit reuptake and increase levels of serotonin, resulting in additive effects with serotonergic drugs.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions3
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

St. John's Wort and Tapentadol

These two interact in 3 distinct ways. Each one is explained separately below.

Why Are There 3 Interactions?

St. John's Wort interacts with whole categories of medication. Tapentadol falls into 3 of those categories, so it can interact with St. John's Wort in 3 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

SEROTONERGIC DRUGS

1 of 3

Why this applies to Tapentadol

Tapentadol falls under SEROTONERGIC DRUGS — the group St. John's Wort interacts with.

Theoretically, St. John's wort might inhibit reuptake and increase levels of serotonin, resulting in additive effects with serotonergic drugs.
Concomitant use of serotonergic drugs with St. John's wort can lead to increased adverse effects and increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstriction disorders.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the thing with tapentadol (Nucynta): besides easing pain like a typical opioid, it also boosts norepinephrine and nudges serotonin signaling in your nervous system. St. John's wort works on serotonin too. Stack the two together and you can get more serotonin activity than your body wants, which raises the risk of what we call serotonin syndrome.

Watch for things like agitation, a racing heart, sweating, shivering, muscle twitching, or confusion. To be clear, this concern is mostly theoretical, based on how these two work rather than lots of real-world cases, so don't panic if you've taken both. Still, since serotonin syndrome can occasionally turn serious, please run this combination by your pharmacist or doctor before mixing them.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Miller LG. Herbal Medicinals: Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-11.
  2. Gordon JB. SSRIs and St. John's Wort: possible toxicity? Am Fam Physician 1998;57:950, 953.
  3. Beckman SE, Sommi RW, Switzer J. Consumer use of St. John's wort: A survey of effectiveness, safety, and tolerability. Pharmacotherapy 2000;20:568-74.
  4. Singhal AB, Caviness VS, Begleiter AF, et al. Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology 2002;58:130-3. PubMed
  5. Sarris J, Ravindran A, Yatham LN, et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety T
Moderate

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES

2 of 3

Tapentadol also falls under CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES.

St. John's wort may increase the metabolism and reduce the levels of CYP2C19 substrates.
Preliminary clinical research in healthy males shows that taking St. John's wort for 14 days induces CYP2C19 and increases metabolism of mephenytoin (Mesantoin). In patients with wild-type 2C19 (2C19*1/*1) metabolism was almost 4-fold greater in subjects who received St. John's wort compared to placebo. In contrast, patients with 2C19*2/*2 and *2/*3 genotypes did not demonstrate a similar increase in metabolism. Theoretically, St. John's wort might increase metabolism of other CYP2C19 substrates.
Severity Moderate Likelihood Possible Evidence B

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the thing with combining St. John's wort and tapentadol (Nucynta). St. John's wort can speed up certain liver enzymes, including one called CYP2C19, which is one of the pathways your body uses to clear tapentadol. In theory, that faster clearance could lower the amount of tapentadol in your system, meaning your pain relief might not last as long or feel as strong as it should.

I want to be straight with you though: this is based on limited, lower quality research, and tapentadol leans more on a different enzyme (CYP2C9) plus simple conjugation, so the real effect may be small. The bigger concern is that both can act on serotonin, raising a small risk of serotonin syndrome. Please don't change anything on your own. Loop in your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Wang LS, Zhu B, Abd El-Aty A, et al. The influence of St. John's wort on CYP2C19 activity with respect to genotype. J Clin Pharmacol 2004;44:577-81. PubMed
Moderate

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES

3 of 3

Tapentadol also falls under CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES.

St. John's wort may increase the metabolism and reduce the levels of CYP2C9 substrates.
There is contradictory research about the effect of St. John's wort on CYP2C9. Some in vitro research shows that St. John's wort induces CYP2C9, but to a lesser extent than CYP3A4. St. John's wort also induces metabolism of the S-warfarin isomer, which is a CYP2C9 substrate. Other research shows that St. John's wort 300 mg three times daily for 21 days does not significantly affect the pharmacokinetics of a single 400 mg dose of ibuprofen, which is also a CYP2C9 substrate. Until more is known, use St. John's wort cautiously in patients who are taking CYP2C9 substrates.
Severity Moderate Likelihood Possible Evidence B

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the gist for tapentadol (Nucynta). St. John's wort can rev up certain liver enzymes, including one called CYP2C9, which is one of the pathways that helps clear tapentadol from your body. Speeding that up could lower the amount of tapentadol in your system, so it may not control your pain as well. For something you're taking specifically to manage moderate to severe or nerve-related pain, that loss of relief matters.

That said, the evidence here is mixed and not strong. Studies disagree on how much St. John's wort actually affects CYP2C9, so this may be a modest effect or even minimal. Still, since this is a pain medicine, please loop in your pharmacist or doctor before combining them rather than adjusting anything on your own.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Henderson L, Yue QY, Bergquist C, et al. St John's wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002;54:349-56..
  2. Foster BC, Vandenhoek S, Hana J, et al. In vitro inhibition of human cytochrome P450-mediated metabolism of marker substrates by natural products. Phytomedicine 2003;10:334-42.. PubMed
  3. Komoroski BJ, Zhang S, Cai H, et al. Induction and inhibition of cytochromes P450 by the St. John's wort constituent hyperforin in human hepatocyte cultures. Drug Metab Dispos 2004;32:512-8. PubMed
  4. Jiang X, Williams KM, Liauw WS, et al. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004;57:592-9. PubMed
  5. Bell EC, Ravis WR, Lloyd KB, Stokes TJ. Effects of St. John's wort supplementation on ibuprofen pharmacokinetics. Ann Pharmacother 2007;41:229-34. PubMed

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

St. John's Wort Also Interacts With Other Medications

St. John's Wort has 755 major, 387 moderate known drug interactions in our database — the Tapentadol one above is among them. If you take anything else, check it against the full list below.

Major 755 Moderate 387 No known interaction 1,688 (incl. Tapentadol)
Taking anything else?

Check Another of Your Medications Against St. John's Wort

Covers the 2,830 medications we’ve checked against St. John's Wort. Pick one to open its full report.

From our Q&A

Questions About St. John's Wort or Tapentadol

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers St. John's Wort or Tapentadol, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Tapentadol

This page covers St. John's Wort only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Tapentadol page lists 113 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Lithium (major), 5-htp (moderate), Acetyl-l-carnitine (moderate) and Adrafinil (moderate).

By severity: 2 major · 84 moderate · 27 minor.

From our pharmacist’s overview on the Tapentadol page

“Tapentadol (Nucynta, Nucynta ER) is an opioid painkiller that also boosts serotonin signaling on its own, and that is exactly where its supplement list bites hardest. The two major-rated entries among the 113 on file deserve a hard look first: lithium, which alongside a serotonergic drug like tapentadol can raise the risk of serotonin…”

Reviewed by 2 · Jul 18, 2026

Open the Tapentadol interaction page

One more smart check

Taking St. John's Wort as Part of a Dietary Supplement Product? Check It for Interactions

We hold 1,159 real supplement products containing St. John's Wort, each one broken down to its full ingredient list — and combination products often carry several ingredients besides St. John's Wort. Your product may carry other ingredients that interact with Tapentadol too, on top of St. John's Wort — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where St. John's Wort and Tapentadol Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement St. John's Wort
Top 25%

#155 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Tapentadol
Top half

#825 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About St. John's Wort

What is St. John's Wort?

St. John's Wort
  • Mild to moderate depression
  • Anxiety and stress
  • Sleep problems
  • Menopausal symptoms
  • Wound healing (topical)

St. John's wort is a well-studied herb most often used for mild to moderate depression, and some research suggests it may help with this. However, it has many serious interactions with prescription medicines and is not safe for everyone, so always talk to your pharmacist or doctor before taking it.

Read the full St. John's Wort monograph & all interactions
Medication

About Tapentadol

What Is Tapentadol Used For?

Brand names: Nucynta, Nucynta ER

Tapentadol tablets (including Nucynta and Tapentadol Hydrochloride tablets) are used for severe acute pain in adults when other treatments are not adequate. Nucynta tablets are also approved for acute pain in children aged 6 and older who weigh at least 40 kg.

Nucynta ER and tapentadol extended-release tablets are used for severe, ongoing pain that requires around-the-clock opioid treatment and cannot be managed with other options, including severe neuropathic pain (nerve pain) caused by diabetic peripheral neuropathy in adults. Extended-release formulations are not intended for as-needed use.

See full Tapentadol drug information
Keep checking

Other Drugs & St. John's Wort

Browse every other medication we’ve checked against St. John's Wort — both the ones with a known interaction and the ones without. Select any drug for the full detail.

755Major
387Moderate
0Minor
1,687No known interaction
755 Major 387 Moderate 1,687 No interaction
Major

755 interactions

Showing 60 of 755 major interactions — see all 755 on the St. John's Wort page.

Moderate

387 interactions

Showing 60 of 387 moderate interactions — see all 387 on the St. John's Wort page.

No interaction 1,687 drugs checked — show the list

We also checked St. John's Wort against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 1,687 medications checked with no known interaction — see the full St. John's Wort list.

See the full St. John's Wort interactions page
See every supplement checked against Tapentadol, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
St. John's Wort monograph › Uses, safety, and every drug interaction in one place Tapentadol supplement interactions › Every supplement checked against Tapentadol, ranked by severity Tapentadol drug information › The full plain-English guide to this medication Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking St. John's Wort and Tapentadol Together: Common Questions

Can you take St. John's Wort with Tapentadol?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 3 interactions listed for St. John's Wort and Tapentadol?
Tapentadol belongs to more than one drug category, and St. John's Wort interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the St. John's Wort and Tapentadol interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Tapentadol and St. John's Wort?

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.